Project Summary/Abstract This proposal describes a four year career development plan and a research strategy for Dr. Sanghyun Lee to transition from a postdoctoral fellow to an independent academic faculty position investigating virus-host interactions. The overall research goal of the proposal is to elucidate the mechanism by which a secreted viral non-structural protein antagonizes host immunity, and to evaluate this viral factor as a novel vaccine target. Candidate: I have focused my science career on understanding virus and host interactions at both molecular and physiological levels. In my Ph.D. work with Dr. Kwangseog Ahn at Seoul National University in Korea, I worked on understanding the virulence of human cytomegalovirus (HCMV), and specifically focused on the factors contributing to HCMV virulence in human patients. As a postdoc in Dr. Skip Virgin's lab at Washington University School of Medicine, I studied the cellular tropism of norovirus and the key host immune system determinants controlling norovirus infection in the gut. Career Development Plan: In addition to the research proposal outlined here, I will devote approximately 15% of my time to training activities. I will continue my professional development under the guidance of my mentor Dr. Virgin's and my co-mentor Dr. Gaya Amarasinghe. I have assembled a career advisory committee composed of Dr. Michael Diamond, Dr. Megan Baldridge, and Dr. Haina Shin that will evaluate and facilitate my research progress and transition to independence. Beyond these training activities, I will prepare to transition to an independent faculty position by improving grant-writing and interviewing skills through workshops at WUSM, and begin planning for the new financial, management, and mentorship responsibilities of an independent investigator. Research Project: Human noroviruses (HNoVs) are the leading global cause of gastroenteritis. However, there are no approved vaccines or therapeutics. With Murine norovirus (MNoV) model, we identified Tuft cells, a rare type of intestinal epithelial cell (IEC), as the reservoir for MNoV fecal shedding and persistence. Genetic studies revealed that viral non-structural protein NS1, rather than a viral surface protein, is the determinant of Tuft cell tropism, and interferon-lambda (IFN-?) to be a key host determinant. Our preliminary data suggests that the NS1 protein is cleaved by host caspase(s) and secreted into the extracellular space, and NS1 blocks IFN-? production. Therefore, we hypothesize that secreted NS1 protein antagonizes IFN-? production, and that this antagonism is the key determinant of in vivo Tuft cell tropism. The long-term goal of this study is to understand the molecular mechanism of NS1 secretion and IFN-? immune evasion by MNoV, and to apply our findings to evaluate secreted NS1 as a candidate for vaccine and therapeutic development in humans.